To better understand the uniqueness of the oral cavity during HIV infection and subsequent therapy, this project will define the functional relationships among HIV, specific soluble host defense molecules and oral bacteria. Building on the data obtained from Projects 1 (Alteration is the salivary proteome in HIV), Project 2 (Effect of HIV and HAART on oral microbial diversity and colonization, and Project 3 (Effect of HIV on soluble mediators and microbes in the Gl tract), this project focuses on antibacterial and antiviral activities in saliva. Questions to be addressed include (1) what can be learned from how the oral cavity responds to HIV that could be useful for other mucosal sites?, (2) how host defense molecules and cytokines are modulated during HIV infection and subsequent therapy?, (3) how antiviral and antibacterial activities change during HIV infection?, and (4) a comparison of the HIV-1 variants in the oral cavity, gut, and blood that may be influenced by local host factors. Ultimately we hope to understand why rectal transmission of HIV is much more efficient than oral transmission and how this information could be used to decrease the rate of HIV infection. In order to accomplish these goals we have proposed the following Specific Aims: Specific Aim 1. To quantitate a subset of soluble innate host factors that are known to interact with both HIV and bacteria Specific Aim 2. To quantitate the anti-HIV and antibacterial activity of samples from HIV-, HIV+, and HIV+/HAART subjects as well as from individual purified proteins and to determine whether oral and rectal tissues differ in their susceptibility to HIV infection in vitro. Specific Aim 3. To characterize genetic and phenotypic features of the HIV reservoir in the oral cavity, blood, and gastrointestinal tract.